Background:　Multicellular　resistance　(MCR),　i.e.　decreased　sensitivity　to　anticancer　drugs　compared　with　common　monolayer　cell　(MC)　cultures,　depends　partly　on　tumor　cell-cell　adhesion.　Previous　studies　have　shown　that　anti-adhesive　therapies,　including　integrin　alpha(v),　beta(1)　and　alpha(v)beta(3)　targeting,　induced　apoptosis　and　reversed　the　sensitivity　of　MCR.　Methods:　A　model　of　three-dimensional　cell　culture　was　used　to　establish　HT29　multicellular　spheroid　cells　(MCS)　and　explore　the　effect　of　semaphorin3F　(Sema3F)　on　integrin-mediated　cell-cell　interactions　in　MCS　of　a　human　colorectal　adenocarcinoma　cell　line　(HT29)　and　sensitization　of　HT29　MCS　to　5-fluorouracil　and　oxaliplatin　via　a　decrease　in　integrin　alpha(v)beta(3).　Results:　Elevated　expression　of　Sema3F　led　to　the　up-regulation　neuropilin-2　(Nrp2)　receptor　expression　and　the　down-regulation　of　integrin　alpha(v)beta(3)　expression.　Furthermore,　short　interfering　RNA　of　Nrp2　could　reverse　MCR.　Conclusion:　Our　study　demonstrates　that　Sema3F　can　sensitize　MCR　by　decreasing　integrin　alpha(v)beta(3)　expression　via　the　Nrp2　receptor.　Copyright　(C)　2009　S.　Karger　AG,　Basel